Anti-Ro and Anti-La in Pregnancy

1. What every clinician should know

Clinical features and incidence

Fetuses exposed to maternal anti-SSA/Ro and/or SSB/La antibodies can develop a disease referred to as neonatal lupus (NL). The term is misleading since the fetus does not have systemic lupus erythematosus (SLE) per se and often neither does the mother. The two most common manifestations of the fetal/neonatal disease involve the skin and the heart, which can be present together but more commonly occur separately.

Other terms for the disease are autoimmune congenital heart block (CHB), complete congenital heart block (CCHB), complete atrioventricular block (CAVB), cardiac-neonatal lupus (cardiac-NL) and neonatal lupus erythematosus (NLE), which usually refers to the skin rash. Abnormal liver function tests and low blood counts can also be part of the syndrome.

Although the spectrum of cardiac abnormalities associated with maternal anti-Ro antibodies is widening as awareness is raised, the signature manifestation is advanced heart block, most often third degree. In about 15% of cases there can be an associated cardiomyopathy. Isolated endocardial fibrosis and valvular abnormalities also have been described in fetuses exposed to anti-Ro antibodies, but these are rarer still and less classic.

In general, standard prenatal evaluation does not include testing for anti-SSA/Ro or SSB/La antibodies. SSA and Ro are interchangeable names for the same protein, as are SSB and La. Most commercial testing is done by ELISA, but labs can differ and some identify anti-Ro60 and others anti-Ro60 as well as anti-Ro52, which are different. There is controversy as to which antibody response carries a higher risk, with some reports favoring the anti-p200 peptide of Ro52. However, it remains unproven whether the latter is more predictive.

The key point is that most commercial labs report on anti-Ro60 when anti-Ro is ordered. High titers are more likely to be associated with disease than low titers. Isolated antibodies to Ro52 are extremely uncommon and thus a positive anti-Ro is sufficient to place the pregnancy at risk. If a laboratory reports a negative anti-Ro60 specifically, it is probably sufficient to stop there, but some investigators in Europe suggest specific testing for anti-Ro52, which may or may not be available in most commercial laboratories.

Risk factors

Mothers who have any autoimmune symptoms whatsoever should be tested, whether they have established SLE, Sjogren's syndrome (SS), rheumatoid arthritis or just have a vague past history that someone told them they had an autoimmune disease, even if never fully diagnosed. Importantly, if the mother tests negative for these autoantibodies, she will not have a child with cardiac manifestations of neonatal lupus. Thus, in a known patient with SLE who does not have anti-Ro antibodies, echocardiographic evaluation is not necessary.

Anti-Ro antibodies are generally present for life, so if you know a mother has these antibodies, they may not need to be tested again. While most women with these antibodies do not have an affected child, it is imperative that anti-Ro be tested if fetal bradycardia is detected and atrioventricular block subsequently confirmed by echocardiogram. The chances the mother will test positive for anti-Ro antibodies (even if totally asymptomatic) is over 80% if there are no structural abnormalities and the block is detected between 18-24 weeks of gestation. Importantly, maternal disease does not seem to influence the chance of developing cardiac NL, only the presence of the antibodies.

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2. Diagnosis and differential diagnosis

Establishing the diagnosis

With regard to cardiac manifestations associated with anti-Ro and or La antibodies, three points are relevant: identifying whether a patient is at risk, deciding upon a surveillance plan, and treating an identified problem. Unfortunately, testing for the candidate maternal autoantibodies is not currently considered part of standard of care. This becomes important since asymptomatic women can have these autoantibodies and some women are only identified to have these antibodies because they are tested when their fetus is found to have an isolated conduction defect.

In aggregate, the best one can do is test all women with any symptoms of a rheumatic disease or even a family history of a rheumatic disease. Although testing varies from lab to lab, a positive result for anti-Ro puts the fetus at risk for cardiac-NL. A high titer increases that risk. Often it is difficult to ascertain whether the titer is high, but a borderline positive is less likely to result in fetal disease; similarly, the finding of only anti-La antibodies without anti-Ro is also less worrisome. In fact, the finding of an isolated anti-La antibody is so unusual as to raise the possibility that it is incorrect. With regard to titer, the following example should be informative.

If the ELISA cutoff is 19 EU for anti-Ro antibodies and the patient's result is 25 EU, the risk is negligible since most women who have affected babies have titers into the thousands. However, some laboratories use very different cutoffs and it becomes difficult to ascertain whether the titer is high or not. If a patient has anti-Ro antibodies by history, it is very unlikely that she will ever become negative. Thus, repeat testing of a known positive woman might not even be necessary.

With regard to estimates of risk, it is generally accepted that the risk of cardiac NL is 2-5% for an anti-Ro positive woman who has either never been pregnant or who has had only previously healthy offspring. If an anti-Ro positive mother has had a previously affected child with cardiac NL, the risk increases to approximately 18%. Importantly, if an anti-Ro positive mother has had a previous child with a skin rash consistent with neonatal lupus, the chance of having a subsequent child with cardiac NL is about 13%. Thus, past history is highly relevant.

The surveillance plan for an anti-Ro positive woman is somewhat controversial. In the optimal situation, serial echocardiograms are recommended for all anti-Ro positive women. Serial echocardiograms should be done most often during the time of increased vulnerability, which is between 18 to 24 weeks. Thus, it has been suggested that weekly echocardiograms be performed between 16-18 through 26 weeks and then every other week until 32-34 weeks of gestation. This aggressive surveillance is based on the fact that third-degree block, once identified, is not reversible.

The justification for a vigilant approach rests on the consideration that an early abnormality can (1) be identified; (2) if left untreated progress to immutable disease; and (3) be reversed with treatment. These qualifications have yet to be uniformly satisfied. However, given the lifelong burden of disease, the chance to prevent or intervene before the situation is irreversible is the only available approach. A disturbing observation that has emerged from current research efforts is the rapidity of disease progression, with advanced heart block and life-threatening cardiomyopathy being observed within a week after detection of a normal sinus rhythm.

The main purpose of the echocardiogram is to measure the mechanical PR interval. In the initial assessment, a complete 2-D echocardiographic and color Doppler study of the fetal heart would be expected to include all standard views to rule out the presence of any structural abnormalities of the fetal heart that could cause congenital heart block, such as L-transposition of the great arteries, atrioventricular septal defect or heterotaxias. In addition, all studies should be reviewed for the presence of pericardial effusions, pleural effusions, ascites or scalp edema. The M-mode study should include views of both ventricles obtained by a perpendicular M-mode at the level of the AV valve leaflets.

The measurements taken from these M-mode recordings include the atrial cycle length as well as the ventricular cycle length and a deduced diagnosis of the heart rhythm. The M-mode study assesses the diameters of the standard views of the left ventricular end diastolic diameter and end systolic diameter. Derived M-mode values include the left ventricular shortening fraction (SF), defined as the left ventricular end diastolic diameter minus the left ventricular end systolic diameter, divided by the left ventricular end diastolic diameter. The lower limit of normal SE is set at 28%.

Doppler study using a pulsed wave of the fetal heart is employed to obtain the mechanical Doppler PR interval measurements. The 2-D directed pulsed Doppler gate is placed distal to the mitral valve within 20º of parallel to the left ventricular outflow tract. By obtaining the pulsed Doppler signal in this location, the mitral valve Doppler flow pattern (specifically, the E/A ratio) is determined, as well as the aortic Doppler pattern on the same simultaneous tracing.

The tracing is frozen and the interval between the onset of the mitral valve A wave and the upstroke of the aortic valve flow is measured. The time interval (in seconds) between these two Doppler samples represents the delay from onset of atrial contraction to onset of ventricular contraction, which is representative of the mechanical PR interval.

The definition of an abnormally prolonged PR interval (ie, the value that would imply the need for treatment) has been debated. At least in many hands, 3 SD above the mean (which is 150 msec) usually triggers immediate discussion. This in utero proxy of a first-degree heart block (as postnatally assessed by EKG) should be discussed in a team approach inclusive of a pediatric cardiologist, obstetrician and rheumatologist. If nothing more, a watchful approach should include a repeat measurement within 24 hours.

If the PR persists at or greater than 150 msec, dexamethasone at 4mg per day should be considered. The echocardiogram should be repeated within a week, and if the PR interval returns to normal, the decision to discontinue dexamethasone and follow with weekly echocardiograms may be reasonable. If there is persistence of first-degree block after several weeks, a watchful approach without dexamethasone would be reasonable. Deterioration to more advanced block suggests that dexamethasone has not been efficacious.

On balance, the goal of the echocardiographic vigilance is to forestall or totally prevent the occurrence of third-degree block. The ideal situation is the first one described above in which a prolonged PR interval returns to normal within a short period of treatment with dexamethasone. It is acknowledged that an abnormal PR interval may in fact revert spontaneously. Other signs of antibody injury inclusive of endocardial fibroelastosis should also raise the consideration of dexamethasone as well as intravenous gamma globulin (IVIG).

In addition to zealous surveillance by echocardiogram, other prophylactic approaches have been considered, though none, including steroids, plasmapheresis or IVIG have a proven record of success. In general these medical strategies have been evaluated in the highest risk patients (those with a previously affected cardiac NL child). Since non-fluorinated steroids do not readily cross the human placenta, the use of drugs such as prednisone or medrol would seem unjustified.

Although the use of fluorinated steroids such as dexamethasone, discussed above, might make biologic sense, the tradeoff of unnecessary exposure for 80% of the pregnancies even in the highest risk mother and potential for maternal side effects such as hypertension, diabetes, bone loss and infection would seem to outweigh benefit. Likewise is the consideration of fetal side effects such as oligohydramnios. Taken together, these considerations mitigate against the use of dexamethasone solely for prophylaxis.

IVIG at 400mg/kg weekly from 12-24 weeks of gestation does not reduce the recurrence rate of cardiac NL. It is unknown whether higher doses, more in the anti-inflammatory range such as 1g/kg, would be efficacious.

A potentially promising approach to prevention is the use of hydroxychloroquine (HCQ). This drug may act to decrease inflammation in a pathway specific to the pathogenesis of cardiac injury. A case-control study suggested a benefit of HCQ in lowering the risk of cardiac-NL in pregnancies of anti-Ro positive patients with systemic lupus erythematosus. Preliminary retrospective data suggest that the recurrence rate of cardiac NL is significantly lower in pregnancies exposed to HCQ.

An ongoing prospective trial is now evaluating the efficacy of 400mg HCQ initiated before 10 weeks of gestation in reducing recurrent cardiac NL. Since HCQ is often used by patients with a variety of rheumatic diseases, this medication is very familiar to rheumatologists who continue its use during pregnancy due to concern that stopping it may result in a disease flare. The issue is whether to begin HCQ in a totally asymptomatic patient who has had a prior child with cardiac NL for the sole purpose of prevention.

It should also be emphasized that if during routine obstetrical screening fetal bradycardia is identified, this should prompt referral for echocardiogram. Any conduction defect should trigger immediate testing of the mother for anti-Ro antibodies regardless of whether the mother has any health issues. A totally healthy woman can have anti-Ro antibodies detected only because her fetus has a conduction defect. It would be reasonable to consult with a rheumatologist if the mother is first identified as having anti-Ro antibodies since she will need to be properly counseled with regard to health issues that might arise in association with these autoantibodies.

In contrast, if a conduction defect is identified and antibodies to Ro and or La are negative, the bradycardia should not be considered a manifestation of neonatal lupus and therapy with dexamethasone would be inappropriate. Given the reversibility of third-degree block, it may not be unreasonable to initiate dexamethasone at 4mg if second-degree block is present or third-degree block is very recently identified, pending evaluation of maternal autoantibodies.

It is important to obtain an EKG and an echocardiogram at the birth of all children exposed to maternal anti-Ro and La regardless of the level of obstetric surveillance. A prolonged PR interval (greater than 150 msec) is of concern and warrants that the child be followed by a cardiologist at least for the first year. While nothing in medicine is absolute, one can generally reassure the mother that if there is no evidence of cardiac injury by 1 week of postnatal life the chances of developing a cardiac problem are quite slim.

With regard to cutaneous involvement, a rash can occur after birth, most often in the second or third postnatal month and following UV exposure. The rash can appear at birth but this is less frequent. The rash is annular in appearance and with rare exception is present on the face or scalp. The absolute tip-off is a rash around the eyes, giving the infant an owl- or raccoon-like appearance.

The rash usually does not require treatment and disappears by about 6-8 weeks coincident with the clearance of the maternal antibodies from the neonatal circulation. Liver abnormalities such as elevated transaminases and low blood counts can also be part of the spectrum of neonatal lupus and are also transient, generally not requiring treatment. A very low platelet count requiring aggressive management is rare but has been observed.

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3. Management

Management of the fetus diagnosed with cardiac-NL is largely based on (a) the likelihood of reversal; (2) prevention of worsening; and (3) side effects of treatment. Although to date third-degree block has not been permanently reversible, it may not be unreasonable to initiate a short course of dexamethasone at 4mg per day if the block is known to be present for less than a week. If there is no change after about 2 weeks of therapy, there may be no justification for continuation.

However, some investigators have suggested that the use of fluorinated steroids is associated with an overall better prognosis and prevention of cardiomyopathy, but this opinion is not universally accepted. In fact, the pendulum has recently swung, with concern that steroids may do more harm than good. Incomplete blocks (second degree) are probably the best suited for therapy with steroids based on the biologic premise that inflammation still outweighs fibrosis in the septal region.

The presence of an associated cardiomyopathy is a poor prognostic sign and generally prompts treatment that can include steroids (some centers advocate as high as 8mg dexamethasone, but 4mg has been more widely reported), IVIG and even plasma exchange. Terbutaline has been used to increase the heart rate but its overall impact is not well established.

4. Complications

As discussed below, the cardiac disease can be fatal. The risk of steroids to both the mother and fetus are discussed above.

5. Prognosis and outcome

Overall, the case fatality rate of cardiac NL ranges from about 17-20%. In utero deaths account for a third of the fatalities, with most occurring before 30 weeks. Fetal echocardiographic variables associated with mortality are endocardial fibroelastosis and hydrops. An earlier time of detection (less than 20 weeks) and heart rates lower than 55 predict a poorer outcome.

Neonatal deaths usually occur before 1 year of life. Of children born alive, the cumulative probability of survival at 10 years is 86%. At 10 years the cumulative probability of requiring a pacemaker is approximately 70%. Most children eventually need a pacemaker but otherwise do very well. Although rare, some children do require cardiac transplantation.

For the asymptomatic mother identified with anti-Ro antibodies solely based on the fetal cardiac dysfunction, referral to a rheumatologist is appropriate. The patient should be counseled that there is a chance she will develop symptoms of a rheumatic disease, often dry eyes and dry mouth. The probability of an asymptomatic mother developing SLE by 10 years is about 19%, and developing probable/definite SS is about 28%. Continued follow-up of asymptomatic NL mothers is warranted since nearly half progress, albeit few develop serious organ-damaging SLE.

6. What is the evidence for specific management and treatment recommendations

(A recently published study from Toronto that provides a counter argument to the treatment of prenatal prolonged PR intervals. The authors report on their experience over a 6-year period in which 142 anti-Ro/La antibody-positive pregnant women were referred for serial fetal echocardiography. The authors concluded that fetal AV prolongation did not predict progressive heart block to birth.)

(This manuscript is similar to the US-based paper on mortality and morbidity but focuses more on the negatives of fluorinated steroids. Variables associated with death were gestational age less than 20 weeks, ventricular rate 50 bpm or less, fetal hydrops and impaired left ventricular function at diagnosis. The presence of one or more of these variables was associated with a 10-fold increase in mortality before birth and a six-fold increase in the neonatal period independent of treatment.)